Inhaled nitric oxide (iNO) therapy is a safe and effective treatment for term newborns with persistent pulmonary hypertension and hypoxemic respiratory failure. However, little is known about the potential role of iNO in the treatment of premature newborns with respiratory failure. Premature newborns are particularly susceptible to the adverse effects of ventilator- induced lung injury, oxygen toxicity, and lung inflammation which contribute to the development of chronic lung disease (CLD). Despite treatment with exogenous surfactant and steroids, CLD remains a major cause of morbidity and mortality in premature newborns. Early clinical observations suggest that low-dose iNO improves oxygenation and decreases the need for mechanical ventilator support in the premature infant. In addition to its effects on gas exchange, recent laboratory and clinical observations suggest that iNO may also act as a lung-specific anti- inflammatory treatment and reduce the contribution of lung inflammation to the evolution of acute and chronic lung injury in premature infants. We recently conducted a masked, randomized, controlled pilot study of low- dose iNO in premature newborns with severe hypoxemic respiratory failure. Eighty patients from 12 centers were randomized to treatment with iNO (5 ppm) or placebo. Low-dose iNO caused acute improvement in oxygenation and reduced ventilator days. Moreover, important trends in CLD reduction were noted in this pilot trial, without an increased incidence of adverse events (e.g. intracranial hemorrhage). Based on the beneficial effects of iNO on gas exchange and lung inflammation, we hypothesize that early treatment with low-dose iNO may reduce the incidence of CLD in premature newborns with respiratory failure. To test this hypothesis, we have designed a multicenter, randomized, controlled, masked trial without crossover. Specific aims of this study are to determine if: l) iNO reduces CLD in premature newborns (gestational age<34 weeks and birth weight 500-1250 grams) with respiratory failure requiring mechanical ventilation in the first 48 hours of life; 2) early serum and tracheal aspirate markers of inflammation are reduced by iNO therapy and predict recovery without CLD; and 3) to assess the safety of iNO. We estimate the incidence of CLD to be 40% for this population. A 25% reduction in CLD disease occurred in our pilot trial. We estimate that a similar reduction in CLD could be achieved in less severely ill newborns. To permit an 80% chance of detecting a 25% reduction in CLD with iNO treatment (40% reduced to 30% with equivalent mortality), 400 patients will be randomized in each group (total n = 800). With 10 centers participating and enrolling a minimum of 30 patients per center per year, the study enrollment duration would be 2 years, 8 months. This study design also allows for insights into the role of inflammatory markers in prediction of CLD risk in the premature newborn.